CN1747933A - New mono-acylated o-phenylendiamines derivatives - Google Patents

Abstract

Objects of the present invention are new mono-acylated o-phenylendiamines derivatives of formula (A) wherein Ar is thiophen-2,5-diyl, pyridine-2,5-diyl, pyridine-5,2-diyl, pyridine-2,6-diyl, pyridine-2,4-diyl or 1,4-phenylene, R<1>, R<2> independently from each other represent hydrogen, C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, C3-12-cycloalkyl, the alkyl, alkenyl, alkynyl and cycloalkyl groups being optionally mono or multiple substituted by hydroxy, halogen, C3-12-cycloalkyl, alkoxy, alkylsulfanyl, acyloxy, alkoxycarbonyl, acyl, C1-6-alkyl-NH-C(O)-, C1-6-alkyl-C(O)NH- or -NR<3>R<4>, or alternatively R<1> is hydrogen, and R<2> is hydroxyl, alkoxy, C2-C12-alkenyloxy or phenoxy, which phenoxy group is optionally substituted with methyl, methoxy, halogen, nitro, cyano, trifluoromethyl, ethenyl or -C(O)-O-CH3, provided that if R<2> is hydroxy, Ar is not thiophen-2,5-diyl; and R<3> and R<4> independently from each other represent hydrogen or C1-6-alkyl, or wherein R<3> and R<4> together with the nitrogen-atom to which they are attached form a ring, which ring is monosubstituted by oxo and which ring may contain a further heteroatom, and pharmaceutically acceptable salts thereof, as well as processes for the manufacturing of these compounds, pharmaceutical compositions containing such compounds and their use in the manufacture of drugs for the treatment of diseases such as cancer.

Description

The new mono-acylated o-phenylendiamines derivative

Purpose of the present invention is new mono-acylated o-phenylendiamines derivatives and pharmacy acceptable salt thereof.The invention still further relates to the compound of these general formula Is the preparation method, contain the pharmaceutical composition of this compounds and be used for the treatment of such as the application in the medicine of this class disease of cancer in preparation.

Therefore cancer is one of main cause of death, has surpassed cardiovascular and cerebrovascular diseases, spends a large amount of expenses and time to have carried out conquering many researchs of cancer.Yet,,, still have great demand to improved anti-cancer therapies such as surgical operation, radiation and chemotherapy although various therapies are arranged.In these therapies, chemotherapy is one of therapy that is used for the treatment of in the main field of cancer.Most of medicine is by suppressing DNA and as a result of damage tumour cell to show its effect from expressing its cytotoxicity.Yet chemotherapy lacks selectivity and the result is that the untoward reaction that is not enough to distinguish between tumour cell and normal cell and show in normal cell has thus limited their application in therapy.Up to now, think and still do not find gratifying medicine and be starved of toxicity with reduction, the better anticarcinogen of tolerance and high therapeutic action thus.

Compound of the present invention is histone deacetylase (HDAC) inhibitor and shows antiproliferative thus and induce the activity of differentiation, thereby causes tumor cell proliferation inhibition, inducing apoptosis and inhibition infringement.

Transcriptional regulatory is the main incident in cytodifferentiation, propagation and the apoptosis.The target of one group of gene transcription activation decision cell and because of this former thereby cause transcribing the tight adjusting that is subjected to various factors.One of regulation mechanism that it relates in this process is the change of DNA tertiary structure, and it influences by the ability of regulating transcription factor and easily entering its target dna fragment transcribes.The integrity of nucleosome is subjected to the acetylize status adjustment of core histones.Under the situation of low acetylize state, nucleosome is combined closely and is not allowed thus and transcribes.On the other hand, the core histones acetylize nucleosome that relaxed causes allowing to transcribe.The acetylize state of histone is subjected to histone acetyl based transferase (HAT) and the control of histone deacetylase (HDAC) equilibrated.Recently, have been found that hdac inhibitor suppresses growth and induces the cancer cells apoptosis of several types, comprises colon cancer cell, T-cell lymphoma cell and erythroleukemia cell.Because apoptosis is the key factor of cancer development, so hdac inhibitor is the desirable reagent (Koyama, Y. etc., Blood 96 (2000) 1490-1495) that is used for cancer therapy as the effective inductor of apoptosis.

Compound of the present invention shows hypotoxicity and effective antiproliferative and cell differentiation activity unexpectedly, it is characterized in that obtaining promoting because of HDAC suppresses to cause acetylize.

Single acetyl as the cytodifferentiation inductor has been described for O-phenylene diamine derivatives among the EP-A 0 847 992.The compound of same type also is the theme of EP-A 0 242 851.Compound described in these applications is almost only for using the benzoic acid derivative single acetyl adjacent crystalline 1,2-phenylene derivatives in generation.Yet, still have the demand that has the compound that improves characteristic to providing, such as the tolerance, hypotoxicity and the low side effect that increase.

Monoacylated o-phenylenediamines is known in the art the precursor as the corresponding benzimidazoles of preparation, and this class preparation method is described in the following document: for example DE-A 2 062 265; FR 2 167 954; Rastogi, R. and Sharma, S., Indian J.Chem., Sect.B, 21B (5) (1982) 485-487; Moll, R. etc., Z.Chem.17 (1977) 133-134; And Hassan, H. etc., Indian J.Chem.39B (2000) 764-768.

Have been found that compound of the present invention is the hdac inhibitor that has antiproliferative and induce differentiation activity, described activity can cause tumor cell proliferation inhibition, inducing apoptosis and suppress infringement.These compounds are used for the treatment of among the human or animal thus such as this class disease of cancer.Treatable tumour example is: colorectal carcinoma; Mammary cancer (comprising advanced breast cancer); Lung cancer (for example gland cancer and comprise nonsmall-cell lung cancer); Prostate cancer comprises terminal illness; Carcinoma of the pancreas; The hematopoiesis tumour of lymph sample pedigree (for example acute lymphoblastic leukemia, B-cell lymphoma, Burkitt lymphoma); Myelocytic leukemia (for example acute myeloid leukaemia (AML)); Thyroid follcular carcinoma; Myelodysplastic syndrome (MSD); Derive from the tumour of mesenchymal cell; Melanoma; Teratocarcinoma; Neuroblastoma; Neurospongioma; Benign tumour of skin (for example keratoacanthoma); Kidney; Ovarian cancer; Bladder cancer; And epidermal carcinoma, but be not limited to them.

The present invention relates to new compound and the pharmacy acceptable salt thereof of general formula A:

Wherein:

Ar is a thiophene-2,5-two bases, pyridine-2,5-two bases, pyridine-5,2-two bases, pyridine-2,6-two bases, pyridine-2,4-two bases or 1,4-phenylene;

R ¹, R ²Represent hydrogen, C independently of one another _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, C _3-12-cycloalkyl, described alkyl, alkenyl, alkynyl and cycloalkyl are optional by hydroxyl, halogen, C _3-12-cycloalkyl, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; Or alternatively

R ¹Be hydrogen; And

R ²Be hydroxyl, alkoxyl group, C ₂-C ₁₂-alkenyloxy or phenoxy group, this phenoxy group optional by methyl, methoxyl group, halogen, nitro, cyano group, trifluoromethyl, vinyl or-C (O)-O-CH ₃Replace, condition is if R ²Be hydroxyl, Ar is not a thiophene-2 so, 5-two bases; And

R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl; Or wherein

R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

Especially the compound of preferred formula I and pharmacy acceptable salt thereof:

Wherein:

Ar is a thiophene-2,5-two bases, pyridine-2,5-two bases, pyridine-5,2-two bases or 1,4-phenylene;

R ¹, R ²Represent hydrogen, C independently of one another _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, C _3-12-cycloalkyl, described alkyl, alkenyl, alkynyl and cycloalkyl are optional by hydroxyl, halogen, C _3-12-cycloalkyl, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted;

R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl; Or wherein

R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

The present invention also comprises pharmacy acceptable salt or the prodrug and the application in producing medicament of these compounds, salt and prodrug of general formula A or compound of Formula I.

The definition of the following general terms that is used for this specification sheets and this term are to occur separately or occur irrelevant with array mode.

Term " C ₁-C ₁₂-alkyl " expression contains the saturated straight chain or the branched-chain alkyl of 1-12 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, 2-butyl, the tertiary butyl, amyl group, hexyl, heptyl etc.Term " C ₁-C ₆Alkyl " expression contains the saturated straight chain or the branched-chain alkyl of 1-6 carbon atom.Alkyl can be chosen wantonly by hydroxyl, halogen, C _3-12-cycloalkyl, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted.The example of the alkyl residue that replaces for example has trifluoromethyl, pentafluoroethyl group, 2-dimethylamino-ethyl, 2-diethylin-ethyl, 2-dibutylamino-ethyl, 2-diisopropylaminoethyl-ethyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, 2-propoxy--ethyl, 3-dimethylamino-propyl group, 3-diethylin-propyl group, 3-dibutylamino-propyl group, 3-diisopropylaminoethyl-propyl group, 3-methoxyl group-propyl group, 3-oxyethyl group-propyl group, 3-propoxy--propyl group, 2-acetylaminohydroxyphenylarsonic acid ethyl, 3-acetylaminohydroxyphenylarsonic acid propyl group (proyl), 2-methoxyl group-1-methyl-ethyl is (with its (R), (S) and (R, S) form), the cyclopropyl methyl, 3-dimethylamino-2, the 2-dimethyl propyl, 3-(2-oxo-tetramethyleneimine-1-yl)-propyl group or 2-(2-oxo-tetramethyleneimine-1-yl)-ethyl.

This class group represented in term " alkoxyl group ", and wherein alkyl residue connects as above-mentioned definition and by Sauerstoffatom.

This class group represented in term " alkyl alkylthio base ", and wherein alkyl residue connects as above-mentioned definition and by sulphur atom.

Term " acyloxy " expression group alkyl-C (O)-O-, wherein alkyl residue is as above-mentioned definition.

Term " carbalkoxy " expression group alkyl-O-C (O)-, wherein alkyl residue is as above-mentioned definition.

Term " acyl group " expression group alkyl-C (O)-, wherein alkyl residue is as above-mentioned definition.

Term " C ₂-C ₁₂-alkenyl " refers to the unsaturated alkyl that contains 2-12 carbon atom and at least one two key, preferred allyl group or pentadienyl.

Term " C ₂-C ₁₂-alkynyl " refer to and contain 2-12 carbon atom and at least one triple-linked unsaturated alkyl, such as Propargyl, preferred proyl.

Term " C ₂-C ₁₂" represent this class group, wherein the alkenyl residue connects as above-mentioned definition and by Sauerstoffatom-alkenyloxy, preferred allyloxy.

Used term " C among the present invention _3-12" expression contains the saturated carbon ring of 3-12 carbon atom to-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.

Term " form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring " refers to heterocycle, such as pyrrolidone-1-base or piperidone-1-base.

Term " halogen " expression chlorine, iodine, fluorine and bromine.

Term " salt of pharmaceutically acceptable sour addition " comprises the salt that forms with mineral acid and organic acid, and described mineral acid and organic acid are all if any hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, toxilic acid, acetate, succsinic acid, tartrate, methylsulfonic acid, tosic acid, amino cyclohexanecarboxylic acid sulfonic acid etc.

Compound of the present invention can contain one or more chiral centres and can exist with racemize or optically-active form thus.Can racemoid be separated into enantiomorph according to known method.Preferably can be by the diastereoisomeric salt of Crystallization Separation by forming by racemic mixture with the optically-active acid-respons, described optically-active acid such as for example D-or L tartrate, amygdalic acid, oxysuccinic acid, lactic acid or camphorsulfonic acid.In addition, can be by AG, half preparation or preparation scale chromatography, use suitable optically active stationary phase and suitable eluent that racemic compound is separated into its enantiomorph.Suitable optically active stationary phase is including, but not limited to silicon-dioxide (ChiraSper for example, Merck; Chiralpak OT/OP, Baker), cellulose esters or amino formate (Chiracel OB/OY for example, Baker) or other (Crownpak for example, Daicel or Chiracel OJ-R, Baker).

The enantiomorph of general formula A or I, diastereomer and racemoid and pharmacy acceptable salt thereof also are integral parts of the present invention.

The general formula I of preferred group or the compound of A are: compound, wherein R ¹Be hydrogen or or alkyl and R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴The above-mentioned definition;

The compound of general formula I or A, wherein R ¹Be hydrogen and R ²Be alkenyl or alkynyl;

Compound, wherein R ¹Be hydrogen and R ²Be unsubstituted straight or branched C _1-12-alkyl or alkoxy, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl;

The compound of general formula I or A, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted C _1-12-alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl; With

The general formula I of claim 1 or the compound of A, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

The compound of preferred formula I, wherein Ar is the thiophene-2 of general formula I-A, 5-two bases:

Wherein:

R ¹Be hydrogen or C _1-6-alkyl; And

R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As above-mentioned definition.

The example of this compounds is:

Embodiment sequence number compound

1-19 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(butyl-first

Base-acid amides)

1-34 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-diethylamide

1-36 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-third

-2-alkynyl-acid amides)

1-37 thiophene-2,5-dicarboxylic acid 2-(allyl group-methyl-acid amides) 5-[(2-amino-

Phenyl)-acid amides]

1-38 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-diformazan

Amino-ethyl)-ethyl-acid amides]

1-39 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-dipropyl acidamide

1-40 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-penta

Base-acid amides)

1-41 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-diethyl

Amino-ethyl)-methyl-acid amides]

1-42 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-[is two-(2-first

Oxygen base-ethyl)-acid amides]

1-44 thiophene-2,5-dicarboxylic acid 2-acid amides 5-[(2-amino-phenyl)-acid amides]

The compound of preferred formula I or A or I-A, wherein R in addition ¹Be hydrogen and R ²Be alkenyl or alkynyl.

This compounds for example has:

Embodiment sequence number compound

1-30 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-Propargyl-acyl

Amine

1-32 thiophene-2,5-dicarboxylic acid 2-allyl group acid amides 5-[(2-amino-phenyl)-acid amides]

The compound of preferred formula I or A or I-A, wherein R in addition ¹Be hydrogen and R ²Be unsubstituted straight or branched C _1-12-alkyl or alkoxy, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

The example of this compounds is:

Embodiment sequence number compound

1-1 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-Ding

Base)-acid amides]

1-6 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(1-methyl-oneself

Base)-acid amides]

1-9 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-methoxyl group-third

Base)-acid amides]

1-10 thiophene-2,5-dicarboxylic acid 2-[(2-kharophen ethyl)-acid amides] 5-[(2-amino-

Phenyl)-acid amides]

1-11 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-ethyl-oneself

Base)-acid amides]

1-13 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1, the 5-dimethyl-

Hexyl)-acid amides]

1-15 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methoxyl group-1-

Methyl-ethyl)-acid amides]

1-20 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-valeramide

1-21 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-butyramide

1-23 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-oxyethyl group-third

Base)-acid amides]

1-24 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-second month in a season-butyramide

1-25 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-heptamide

1-26 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-pelargonamide

1-27 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-decoylamide

1-28 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-(1-methyl-heptan

Base)-acid amides]

1-29 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(isobutyramide)

1-31 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-propionic acid amide

1-35 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methyl-Ding

Base)-acid amides]

The compound of preferred formula I or A or I-A, wherein R in addition ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted C _1-12-alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

The example of this compounds is:

Embodiment sequence number compound

1-2 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(4-diethylin

-1-methyl-butyl)-acid amides]

1-3 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(3-diethylin-

Propyl group)-acid amides]

1-4 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(3-dibutylamino-

Propyl group)-acid amides]

1-5 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(3-dimethylamino

Propyl group)-acid amides]

1-8 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(3-diisopropyl ammonia

The base ethyl)-acid amides]

1-17 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(3-dimethylamino

-2, the 2-dimethyl propyl)-acid amides]

1-18 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-dimethylamino

Ethyl)-acid amides]

The compound of preferred formula I or A or I-A, wherein R in addition ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

The example of this compounds is:

Embodiment sequence number compound

1-22 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-{[3-(the 2-oxo-

Tetramethyleneimine-1-yl)-propyl group]-acid amides }

The compound of preferred formula I or A or I-A, wherein R in addition ¹Be hydrogen or alkyl and R ²Be cycloalkyl or the alkyl that is substituted by cycloalkyl.This compounds for example is:

1-7 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles heptamide

1-12 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-cyclooctylamine

1-14 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles valeramide

1-33 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles butyramide

1-43 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(the cyclopropyl methyl-

Propyl group-acid amides)

1-16 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-cyclopropyl methyl-

Acid amides

The compound of preferred formula I or A in addition, wherein Ar is the pyridine-2 of general formula I-B, 5-two bases:

Wherein:

R ¹Be hydrogen or alkyl; And

R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As above-mentioned definition.

The example of this compounds is:

2-3 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(butyl-methyl-acyl

Amine)

2-14 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-dipropyl acidamide

2-16 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(methyl-amyl group-acyl

Amine)

2-17 pyridine-2,5-dicarboxylic acid 2-(allyl group-methyl-acid amides) 5-[(2-amino-phenyl)-

Acid amides]

2-18 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-and acid amides] 2-[is two-(the 2-methoxyl group-

Ethyl)-acid amides]

2-19 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-diethylin second

Base)-methyl-acid amides]

The compound of preferred formula I or A or I-B, wherein R in addition ¹Be hydrogen and R ²Be alkenyl or alkynyl.

The example of this compounds is:

2-4 pyridine-2,5-dicarboxylic acid 2-allyl group acid amides 5-[(2-amino-phenyl)-acid amides]

The compound of preferred formula I or A or I-B, wherein R in addition ¹Be hydrogen and R ²Be unsubstituted straight or branched C _1-12-alkyl or by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-Alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

The example of this compounds is:

2-2 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-hexyl acid amides

2-7 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-methoxyl group-second

Base)-acid amides]

2-8 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(3-butoxy-third

Base)-acid amides]

2-9 { [5-(2-amino-phenyl amino formyl radical)-pyridine-2-carbonyl]-amino }-acetate

Methyl esters

2-10 3-{[5-(2-amino-phenyl amino formyl radical)-pyridine-2-carbonyl]-amino }-third

Tert-butyl acrylate

2-11 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2,2,3,3,3-five fluorine

-propyl group)-acid amides]

2-12 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2,2,3,3,4,4,4-

Seven fluoro-butyl)-acid amides]

2-13 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(1, the 5-dimethyl-oneself

Base)-acid amides]

2-15 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(1-methyl-hexyl)-

Acid amides]

2-20 pyridine-2,5-dicarboxylic acid 2-[(2-kharophen ethyl)-acid amides] 5-[(2-amino-benzene

Base)-acid amides]

The compound of preferred formula I or A or I-B, wherein R in addition ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

The example of this compounds is:

2-1 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-[(2-diisopropylaminoethyl

-ethyl)-acid amides]

2-6 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-[(3-dibutylamino-

Propyl group)-acid amides]

The compound of preferred formula I or A or I-B, wherein R in addition ¹Be hydrogen and R ²Be cycloalkyl.

The example of this compounds is:

2-5 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-cyclooctylamine

The compound of preferred formula I or A in addition, wherein Ar represents the pyridine-5 of general formula I-C, 2-two bases:

Wherein:

R ¹Be hydrogen or alkyl; And

R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As above-mentioned definition.

The example of this compounds is:

3-23 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(butyl-methyl-acyl

Amine)

3-24 pyridine-2,5-dicarboxylic acid 5-(allyl group-methyl-acid amides) 2-[(2-amino-phenyl)-acyl

Amine]

3-25 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-Propargyl-

Acid amides)

3-26 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-[is two-(2-methoxyl group second

Base)-acid amides]

3-27 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-amyl group-acyl

Amine)

3-29 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-dipropyl acidamide

3-30 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-diethylin second

Base)-methyl-acid amides]

The compound of preferred formula I or A or I-C, wherein R in addition ¹Be hydrogen and R ²Be alkenyl or alkynyl.

The example of this compounds is:

3-2 pyridine-2,5-dicarboxylic acid 5-allyl group acid amides 2-[(2-amino-phenyl)-acid amides]

The compound of preferred formula I or A or I-C, wherein R in addition ¹Be hydrogen and R ²For unsubstituted alkyl or by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

The example of this compounds is:

3-3 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-hexyl acid amides

3-6 pyridine-2,5-dicarboxylic acid 5-[(2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides] 2-[(2-amino-benzene

Base)-acid amides]

3-7 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,2,3,3,3-five fluoro-

Propyl group)-acid amides]

3-8 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,2,3,3,4,4,4-seven

The fluoro-butyl)-acid amides]

3-9 3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-butyric acid

Ethyl ester

3-10 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-hydroxyl-propyl group)-

Acid amides]

3-11 2-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-the 3-first

Base-methyl-butyrate

3-12 3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-propionic acid

Ethyl ester

3-13 { [6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-acetate first

Ester

3-14 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methoxyl group-second

Base)-acid amides]

3-15 2-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-the 4-first

Base sulfane base-methyl-butyrate

3-16 3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-propionic acid

The tert-butyl ester

3-17 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,3-dihydroxyl-third

Base)-acid amides]

3-18 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-butoxy-third

Base)-acid amides]

3-21 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-second month in a season-butyramide

3-22 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1, the 5-dimethyl-oneself

Base)-acid amides]

3-31 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-hexyl)-

Acid amides]

The compound of preferred formula I or A or I-C, wherein R in addition ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

The example of this compounds is:

3-1 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-diisopropylaminoethyl-

Ethyl)-acid amides]

3-5 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-dimethylamino-second

Base)-acid amides]

3-19 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-diethylin-1-

Methyl-butyl)-acid amides]

3-20 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dibutylamino-third

Base)-acid amides]

The compound of preferred formula I or A or I-C, wherein R in addition ¹Be hydrogen or alkyl and R ²Be cycloalkyl.

The example of this compounds is:

3-4 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-cyclooctylamine

3-28 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(cyclopropyl methyl-third

Base-acid amides)

The compound of preferred formula I or A in addition, wherein Ar represents 1,4-phenylene, the i.e. compound of general formula I-D

Wherein:

R ¹Be hydrogen or alkyl; And

R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As above-mentioned definition.

The example of this compounds is:

4-13 N-(2-amino-phenyl)-N '-butyl-N '-methyl-terephthalamide

The compound of preferred formula I or A or I-D, wherein R in addition ¹Be hydrogen and R ²Be alkenyl or alkynyl.

This compounds for example is:

4-11 N-allyl group-N '-(2-amino-phenyl)-terephthalamide

The compound of preferred formula I or A or I-D, wherein R in addition ¹Be hydrogen and R ²Be unsubstituted straight or branched alkyl or alkoxy, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

The example of this compounds is:

4-5 N-(2-amino-phenyl)-N '-(2-methoxyl group-1-methyl-ethyl)-terephthalamide

4-7 N-(2-amino-phenyl)-N '-(3-oxyethyl group-propyl group)-terephthalamide

4-12 N-(2-amino-phenyl)-N '-butyl-terephthalamide

The compound of preferred formula I or A or I-D, wherein R in addition ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

The example of this compounds is:

4-1 N-(2-amino-phenyl)-N '-(2-diisopropylaminoethyl-ethyl)-terephthalamide

4-2 N-(2-amino-phenyl)-N '-(3-dibutylamino-propyl group)-terephthalamide

4-3 N-(2-amino-phenyl)-N '-(4-diethylin-1-methyl-butyl)-paraphenylene terephthalamide

Amine

4-4 N-(2-amino-phenyl)-N '-(3-diethylin-propyl group)-terephthalamide

4-8 N-(2-amino-phenyl)-N '-(2-dimethylamino-ethyl)-terephthalamide

4-10 N-(2-amino-phenyl)-N '-(3-dimethylamino-2,2-dimethyl-propyl group)-to benzene two

Methane amide

The compound of preferred formula I or A or I-D, wherein R in addition ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

The example of this compounds is:

4-9 N-(2-amino-phenyl)-N '-[3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-to benzene two

Methane amide

The compound of preferred formula I or A or I-D, wherein R in addition ¹Be hydrogen, alkyl or alkenyl and R ²Be cycloalkyl or the alkyl that is substituted by cycloalkyl.

This compounds for example is:

4-6 N-(2-amino-phenyl)-N '-cyclopropyl methyl-terephthalamide

Another embodiment of the invention is the compound of general formula I-E:

Wherein:

Ar is a thiophene-2,5-two bases, pyridine-2,5-two bases, pyridine-2,6-two bases, pyridine-2,4-two bases, pyridine-5,2-two bases or 1,4-phenylene; And

R ²Expression hydroxyl, alkoxyl group, C ₂-C ₁₂-alkenyloxy or phenoxy group, condition are if R ²Be hydroxyl, Ar is not a thiophene-2 so, 5-two bases.

The example of this compounds is:

5-1 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methoxyl group-acid amides)

5-2 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(oxyethyl group-acid amides)

5-3 thiophene-2,5-dicarboxylic acid 2-(allyloxy-acid amides) 5-[(2-amino-phenyl)-acid amides]

5-4 thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(phenoxy group-acid amides)

5-5 pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-oxyamide

5-6 pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-oxyamide

5-7 pyridine-2,6-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 6-oxyamide

5-8 pyridine-2,4-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 4-oxyamide

Another embodiment of the invention is the compound of general formula I or A:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(uncle-butoxy-acid amides);

Pyridine-2,5-dicarboxylic acid 2-(allyl group-cyclopentyl-acid amides) 5-[(2-amino-phenyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(cyclopropyl methyl-propyl group-acid amides);

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-second month in a season-butyramide;

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-hydroxyl-ethyl) acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-{[2-(2-hydroxyl-oxyethyl group)-ethyl]-acid amides };

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-cyclohexyl methyl-2-hydroxyl-ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-hydroxyl-butyl) acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-hydroxymethyl-2-methyl-butyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(4-hydroxy-cyclohexyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(2-[pair-(2-hydroxyl-ethyl)-amino]-ethyl }-acid amides);

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-dimethylamino-ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-dimethylaminoethyl)-ethyl-acid amides].

Aromatic dicarboxylic acid derivative or its pharmacy acceptable salt that can prepare general formula I or A by any means that becomes known for preparing chemically relevant compound.These class methods that will be used to prepare the aromatic dicarboxylic acid derivative of general formula I or A or its pharmacy acceptable salt provide as another feature of the present invention and explain by following representational embodiment, wherein except as otherwise noted, and Ar, R ¹And R ²Has above-mentioned implication.Can obtain raw material by standard organic chemistry step.The preparation of this class raw material is described in the appended examples.On the other hand, can obtain necessary raw material by the step similar with belonging to the explanation of organic chemistry filed those of ordinary skill.

(a) a kind of preferred method that is used to produce general formula I or A comprises the compound that makes general formula I I and the compound reaction of general formula III, and wherein the structural formula of general formula I I compound is as follows:

Wherein Ar, R ¹And R ²As above-mentioned definition;

Wherein the structural formula of compound of formula III is as follows:

Wherein Y represents hydrogen or suitable amino protecting group.

Become known for amino protecting group from chemistry of peptides; this class protecting group for example is that carbobenzoxy-(Cbz) (by hydrogenation or the Hydrogen bromide cracking in acetate), uncle-butoxy carbonyl (are used the strong acid cracking; such as the HCl in pure trifluoroacetic acid or trifluoroacetic acid in methylene dichloride or the Zai diox), 9-fluorenylmethyloxycarbonyl (with the cracking of secondary amine class, such as piperidines).

If the R on the general formula A ²Be OH, this hydroxyl can have and be used for HNR as described below so ¹R ²Protecting group with compound V or VI reaction.Wherein hydroxyl protecting group is can be by the benzyl oxide of hydrocracking.The protected HNR of some O- ¹R ²Group, be purchased such as O-benzyl oxyamine.

This reaction generally comprises two steps, one jar of step.In a first step, activate this compound by the carboxylicesters reaction in the inert solvent that has activator to exist or thinner, for example methylene dichloride, diox or tetrahydrofuran (THF) that makes general formula I I.

The reactive derivatives of suitable acid is: acyl halide for example, for example chloride of acid by acid and inorganic acyl chlorides, for example thionyl chloride or the reaction of oxalyl dichloro are formed; The blended acid anhydrides is for example by making acid react the acid anhydrides that forms with chloro-formic ester, such as isobutyl chlorocarbonate; Active ester is for example by making acid react the ester that forms with phenol, such as Pentafluorophenol; By the active ester that acid and the reaction of N-hydroxybenzotriazole are formed; Acid azide is for example by making acid react the trinitride that forms with trinitride, such as diphenylphosphine acyl group nitride; Acyl cyanide is for example by making acid react the prussiate that forms with prussiate, such as diethyl phosphoryl prussiate; Or acid and carbodiimide, the product that reacts such as N-3-dimethylamino-propyl N-ethyl carbodiimide or dicyclohexylcarbodiimide; Or acid and N, the reaction product of N '-N,N'-carbonyldiimidazole; Or acid and uronium salt, such as O-(1H-benzotriazole-1-yl)-N, N, N ', the reaction product of N '-tetramethyl-nitronium tetrafluoroborate; Or acid with based on the reagent of phosphorus, for example pair-reaction product of (2-oxo-3-oxazolidinyl)-phosphoryl chloride.This is reflected at-30 ℃-60 ℃, carries out being lower than under 0 ℃ usually.

In second step, compound III is joined in the solution that contains activated acids.If Y is a protecting group, so finally must be with its cracking (method referring to above) to obtain Compound I.In order to obtain R ²Be the compound of hydroxyl, amino-as to may reside on the molecule with hydroxyl protecting group.In this case, must use aforesaid method cracking hydroxyl protecting group before amino protecting group.

These methods are that those skilled in the art are well-known.Being used for synthetic all methods as the used amides of chemistry of peptides described in " Methoden der organischen Chemie (Houben-Weyl) " B and XV/1 and XV/2 in principle also is suitable for.The monoacylated of protected phenylenediamine is not described among the EP0974576.

(b) can prepare the compound of general formula I I by compound hydrolysis from general formula I V:

R wherein ³Be alkyl or aralkyl, preferable methyl, ethyl, tert-butyl, benzyl.

According to radicals R ³The difference of character is implemented cracked condition difference.Work as R ³During for alkyl, such as methyl or ethyl, be reflected in inert solvent that alkali exists or the thinner and carry out, described alkali for example is lithium hydroxide, sodium hydroxide or potassium hydroxide, and described inert solvent or thinner for example are MeOH, ethanol, diox, THF, water.Work as R ³During for tert-butyl, be reflected at acid, for example hydrochloric acid and carry out in the presence of at inert solvent, such as the solution in ether Huo diox or the trifluoroacetic acid in methylene dichloride.Work as R ³During for benzyl, reaction by noble metal catalyst is arranged, such as palladium or platinum/suitable carriers, carry out such as hydrogenation in the presence of the carbon.Be used for esterolytic method and depend on residue R certainly ¹And R ²Character.

(c) by the compound of the compound general formula I V of general formula V, wherein Ar and R ³Has above-mentioned implication.

This reaction generally comprises two steps, one jar of step.In a first step, by using the carboxylicesters of the method activation general formula V described in (a).

In second step, be used under the activatory temperature R ¹And R ²General formula HNR with above-mentioned implication ¹R ²Amine join in the solution and and slowly be adjusted to envrionment temperature temperature.Can be with suitable scavenging agent alkali, join in the reaction mixture as triethylamine or diisopropylethylamine.These methods are that those skilled in the art are well-known.Being used for synthetic all methods as the used amides of chemistry of peptides described in " Methoden derorganischen Chemie (Houben-Weyl) " B and XV/1 and XV/2 in principle also is suitable for.

(d) there is the compound of the general formula V described in several documents certainly.For example, terephthalic acid one methyl esters is described in Holba, and V. etc. are among Z.Phys.Chem.262 (1981) 445-448.It also can be for being purchased.Pyridine-2,5-dicarboxylic acid 5-methyl esters for example is described among the WO 93/21146.Thiophene-2,5-dicarboxylic acid one methyl esters for example is described in US 2,680, in 731.Usually preparing these ester classes by selectivity saponification diester, also is that those skilled in the art are well-known but also can use other method and these methods.

(e) the another kind of preferred method that is used to produce general formula I or A compound comprises compound and the general formula HNR that makes general formula VI ¹R ²Amine reaction, the structural formula of its formula of VI compound is as follows:

Wherein Ar such as above-mentioned definition and Y is as (a) described in suitable protecting group;

At general formula HNR ¹R ²Amine in, R ¹And R ²Has implication defined above.

This reaction generally comprises two steps, one jar of step and carries out according to the method described in (a).

Finally must obtain Compound I by aforesaid method cracking Y.As mentioned above, if amino-and hydroxyl protecting group be present on the molecule, so should be before amino protecting group the cracking hydroxyl protecting group.

(f) can be as prepare the compound of general formula VI as described in (b) by compound hydrolysis from general formula VII:

R wherein ³Has above-mentioned implication with Y.

G) by the compound of the compound general formula VII of the compound of general formula V and general formula III, wherein A and R ³Have implication defined above, the structural formula of its formula of V compound is as follows:

Wherein the structural formula of compound of formula III is as follows:

Wherein Y represents the suitable protecting group described in (a).

This reaction generally comprises two steps, the one jar of step described in (a).

Useful additive salt has the valuable pharmacological characteristic on the compound of general formula I or A and the medicine thereof.Have been found that they have antiproliferative and the activity of inducing differentiation, this class activity can cause tumor cell proliferation inhibition, inducing apoptosis and suppress infringement, and these compounds are used for the treatment of in the humans and animals such as this class disease of cancer.

Use cell acetylize test to confirm the activity of The compounds of this invention as hdac inhibitor.Wherein monitor the acetylation of histone in the PC3 cell.Highly acetylated relevant with compound inhibition of histone deacetylase.Parallel monitoring cell survival rate is with the cytotoxicity of assessment compound.

With the PC3 cell, to be the PC-3 be seeded in the RPMI 1640 (comprising 5%FCS, 2mM glutamine and penicillin/streptomycin) in the microtiter plate of 384-hole with 1800 cells/well.

At 37 ℃ after following 48 hours, adding prediluted compound to final concentration is 1uM.With the pre-diluted compounds of methyl-sulphoxide (DMSO), obtain the final concentration in 0.5%DMSO/ hole.

After insulation 24 hours, measure cell survival rate by adding cell proliferation reagent WST-1 (Roche MolecularBiochemicals).Through after 60 minutes, measure optical density(OD) (OD) (450nm and 690nm) again.

After the mensuration, the preparation cellular layer is used for the ELISA reaction.The suction substratum also was fixed on cell in the ethanol 60 minutes under-20 ℃.With after the PBS/Tween washing, add lock solution (PBS/5%FCS/Tween) and washed cell layer once more.Add down by the anti-acetylated histones H3 of dilution in 1: 200 or the antibody (rabbit polyclonal IgG, Upstate Biotechnologie) of H4 at 37 ℃, continue 60 minutes.The HRP conjugate (Dako) that uses the absorption of goat anti-rabbit igg (H+L) human IgG is as secondary antibodies (by dilution in 1: 2000).With cell washing 3 times and make peroxidase substrate ABTS 37 ℃ of down reactions 30-60 minute.Measure OD at the 405nm place.

Acetylize per-cent behind the blank O.D. of calculating deduction:

The embodiment sequence number	The compound title	Cell acetylize (PC3,1 μ M) [control %]
				Reference compound 4-acetylaminohydroxyphenylarsonic acid N-(2-amino-phenyl)-benzamide	152
1-1	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-butyl)-acid amides]	137.2
			1-4	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dibutylamino-propyl group)-acid amides]	195.7
1-6	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-hexyl)-acid amides]	122.9
			1-17	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dimethylamino-2, the 2-dimethyl propyl)-acid amides]	149.8
1-18	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-dimethylaminoethyl)-acid amides]	233.9
			1-19	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acyl	118.8

	Amine] 5-(butyl-methyl-acid amides)
			1-24	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-second month in a season-butyramide	211.2
1-35	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methyl-butyl)-acid amides]	135.4
			1-44	Thiophene-2,5-dicarboxylic acid 2-acid amides 5-[(2-amino-phenyl)-acid amides]	185.6
2-1	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-diisopropylaminoethyl-ethyl)-acid amides]	206.6
			3-1	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-diisopropylaminoethyl-ethyl)-acid amides]	244.8
3-5	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-dimethylamino-ethyl)-acid amides]	154.6
			3-9	3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-ethyl butyrate	211.6
3-20	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dibutylamino-propyl group)-acid amides]	223.8
			4-1	N-(2-amino-phenyl)-N '-(2-diisopropylaminoethyl-ethyl)-terephthalamide	399.3

The new compound of general formula I or A and pharmacy acceptable salt thereof can be used as medicine, i.e. pharmaceutical dosage forms.Can give these pharmaceutical preparations with the liquid or solid form by rectum or parenteral.In this respect, all form of administration commonly used all should consider, such as, for example: tablet, capsule, coating tablet, syrup, solution, suspensoid, suppository etc.Contain the additive that is usually used in injection solution such as this class of stablizer, solubilizing agent and buffer reagent and be preferably used as injectable media.

This class additive for example is: tartrate and citrate buffer, ethanol, coordination agent (such as ethylenediamine tetraacetic acid (EDTA) and atoxic salt thereof), be used to regulate the high molecular polymer (such as the liquid macrogol class) of viscosity.The liquid carrier material that is used for injection solution must be aseptic and preferably allocate it into ampoule.The solid carrier material for example is starch, lactose, mannitol, methylcellulose gum, talcum, high dispersive silicic acid, high molecular weight fatty acid (such as stearic acid), gelatin, agar, calcium phosphate, Magnesium Stearate, animal and plant oil, solid high molecular polymer (such as polyethylene glycols); The appropriate formulation that is used for oral application can also be chosen wantonly and contain sweetener and sweetener.

Containing the compound of general formula I or A or the medicament of its pharmacy acceptable salt and treatment inert support also is purpose of the present invention, as its production method, comprise the compound of one or more general formula Is or A and/or its pharmaceutically-acceptable acid addition and also one or more other treatment is gone up valuable material if desired and make the galenic form of administration with one or more treatment inert supports.

The compound of general formula I of the present invention or A and pharmacy acceptable salt thereof are based on HDAC inhibition and antiproliferative thus and induce differentiation activity to be used for control or preventing disease, described activity can cause that tumor cell proliferation suppresses, inducing apoptosis and suppress infringement, and these compounds are used for the treatment of among the human or animal such as such as this class disease of cancer and be used to produce corresponding medicine.

Dosage depends on various factors, such as administering mode, kind, age and/or individual health situation.Every day, dosage was about 5-400mg/kg, preferred about 10-100mg/kg and can single-dose or be distributed in the administration process several times.

Explain the present invention with the following example now, wherein except as otherwise noted, carry out according to the following step:

I) evaporate and after removing by filter, finish the post-treatment step by rotary evaporation in a vacuum such as this class residual solid of siccative;

(ii) envrionment temperature, be 18-25 ℃ down and rare gas element, operate in such as argon gas or nitrogen environment;

(iii) use available from E.Merck, Darmstadt, the Merck Kieselgel silica gel of Germany or Merck Lichroprep RP-18 reverse phase silica gel carry out column chromatography (by hurried method) and high performance liquid chromatography (HPLC);

(iv) productive rate only is used for task of explanation and needn't be obtainable maximum value;

(v) use the automatic fusing point instrument of Mettler SP62, oil bath equipment or Kofler hot-plate instrument to measure fusing point;

(vi) confirm the structure of general formula I or A product by nuclear (being generally proton) mr (NMR) and mass-spectrometric technique (using the Micromass Platform II type machine of APCI or the Micromass Platform ZMD of use electrospray);

(vii) general incomplete sign intermediate and estimate purity by tlc;

(viii) use following abbreviation:

DMF N, dinethylformamide

The DMSO methyl-sulphoxide

The THF tetrahydrofuran (THF)

MeOH methyl alcohol

HCl hydrochloric acid

The NaH sodium hydride

CH ₂Cl ₂Methylene dichloride

H ₂SO ₄Sulfuric acid

Sat. saturated

Sol. solution

H hour

D days

The rt room temperature

The eq equivalent

Embodiment 1

The preparation of general formula I-A compound

Step 1: 5-(uncle 2--butoxy carbonyl amino-phenyl amino formyl radical)-thiophene-2-carboxylic acid methyl esters

In ar gas environment, 21.0g (129mmol) N,N'-carbonyldiimidazole is joined 24.1g (129mmol) thiophene-2, in the solution of 5-dicarboxylic acid one methyl esters in 600ml THF.Under rt, behind the 2h, add 26.9g (129mmol) (2-amino-phenyl)-t-butyl carbamate also with this reaction mixture restir 4h under rt.Evaporating solvent also is dissolved in the 500ml ethyl acetate with resistates.With the saturated NaHCO of 100ml ₃The aqueous solution with organic phase washing 3 times, wash with water 2 times and use dried over sodium sulfate.Solvent is reduced to 80ml, begins crystallization this moment.Behind the 12h, filter out crystal and use a small amount of ice-cold t-butyl methyl ether and cold heptane wash.It is dry and obtain 38.9g (103.4mmol) 5-(uncle 2--butoxy carbonyl-amino-phenyl amino formyl radical)-thiophene-2-carboxylic acid methyl esters in high vacuum, ¹H-NMR (D ₆-DMSO) δ=1.45 (s, 9H), 3.87 (s, 3H), 7.14 (m, 1H), 7.22 (m, 1H), 7.46 (m, 1H), 7.59 (m, 1H), 7.89 (m, 1H), 7.96 (m, 1H), 8.73 (br, 1H), 10.02 (s, 1H).

Step 2: 5-(uncle 2--butoxy carbonyl amino-phenyl amino formyl radical)-thiophene-2-carboxylic acid

In 20 minutes, in 18.5g (50mmol) 5-(uncle 2--butoxy carbonyl amino-phenyl-formamyl)-suspension of thiophene-2-carboxylic acid methyl esters in 500ml MeOH, add the solution of 5.6g (100mmol) potassium hydroxide in 100ml water.This reaction mixture is at room temperature stirred 2d.Evaporation MeOH also extracts remaining aqueous solution 3 times and with 3N HCl acidified aqueous solution with ethyl acetate.Filter out precipitation, wash with water and dry and obtain 14.5g (40mmol) 5-(uncle 2--butoxy carbonyl amino-phenyl amino formyl radical)-thiophene-2-carboxylic acid in 45 ℃ and high vacuum, ¹H-NMR (D ₆-DMSO) δ=1.45 (s, 9H), 7.14 (m, 1H), 7.22 (m, 1H), 7.46 (m, 1H), 7.59 (m, 1H), 7.90 (m, 2H), 8.72 (s, 1H), 9.99 (s, 1H), 13.54 (s, 1H).

Step 3: (2-{[5-(1-methyl-butyl formamyl)-thiophene-2-carbonyl]-amino }-phenyl)-carboxylamine uncle-butyl ester

In 4.4g (12.1mmol) 5-(uncle 2--butoxy carbonyl amino-phenyl amino formyl radical)-solution of thiophene-2-carboxylic acid in 80ml THF, add 2.2g (13.6mmol) N,N'-carbonyldiimidazole.This reaction mixture is stirred 1h down and is cooled to rt then at 45 ℃.After adding 1.05g (12mmol) 2-amylamine, this reaction mixture is kept 12h under rt.Evaporating solvent also is dissolved in 150ml CH with resistates ₂Cl ₂Each with 150ml water twice of this solution washing also obtained with the ether debris (2-{[5-(1-methyl-butyl formamyl)-thiophene-2-carbonyl]-amino-phenyl)-carboxylamine uncle-butyl ester, be white solid, mp.183 ℃.

Step 4: thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-butyl)-acid amides] (compound 1-1)

Under cooling conditions to 3.3g (7.65mmol) (2-{[5-(1-methyl-butyl formamyl)-thiophene-2-carbonyl]-amino-phenyl)-add the solution in the 4M HCl Zai diox of 16ml in the solution of carboxylamine uncle-butyl ester in 80ml MeOH.With this solution after stirring 3h under the rt, evaporating solvent.The 1M NaHCO that in resistates, adds 50ml methylene dichloride and 50ml ₃The aqueous solution.Under rt, stir after 30 minutes, filter out precipitation, wash with water and be dried to and obtain 2.3g (6.9mmol) thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-butyl)-acid amides], mp.192 ℃, calculated value MW (M+H) 332.14, measured value (M+H) 332.2; ¹H-NMR (400MHz, (CH ₃) ₂SO): δ=9.77 (s, 1H), 8.33 (d, J=8.6Hz, 1H), 7.92 (m, 1H), 7.78 (m, 1H), 7.13 (m, 1H), 6.99 (m, 1H), 6.78 (m, 1H), 6.59 (m, 1H), 4.96 (s, 2H), 3.97 (m, 1H), 1.57-1.39 (m, 2H), 1.36-1.26 (m, 2H), 1.14 (d, J=6.6Hz, 3H), 0.88 (t, J=7.1Hz, 3H).

If the preparation following compounds, so according to carrying out with the similar mode of the step 1-4 of embodiment 1, use proper raw material:

Sequence number	Title	Calculated value MW (M+H)	Measured value MW (M+H)
				1-2	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-diethylin-1-methyl-butyl)-acid amides]; H-NMR (400MHz, (CH 3) 2SO)：δ＝9.75(s，1H)，8.33(d，	403.22	403.1

	J＝8.6Hz，1H)，7.91(m，1H)，7.78 (m，1H)，7.13(m，1H)，6.98(m， 1H)，6.78(m，1H)，6.59(m，1H)， 4.93(s，2H)，3.97(m，1H)， 2.46-2.33(m，6H)，1.53-1.38(m， 4H)，1.15(d，J＝6.6Hz，3H)，0.93 (t，J＝7.1Hz，6H)；
				1-3	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-diethylin-propyl group)-acid amides]; 1H-NMR(400MHz，(CH 3) 2SO)：δ＝ 9.76(s，1H)，8.65(t，J＝5.05Hz， 1H)，7.92(m，1H)，7.71(m，1H)， 7.13(m，1H)，6.99(m，1H)，6.78 (m，1H)，6.59(m，1H)，4.93(s，2H)， 3.27(m，2H)，2.46(q，J＝7.07HZ， 4H)，2.43(t，J＝7.83，2H)，1.64(m， 2H)，0.95(t，J＝7.33Hz，6H)	375.19	375.1
1-4	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dibutylamino-propyl group)-acid amides]	431.25	431.1
				1-5	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(3-dimethylamino-propyl)-acid amides]	347.15	347.3
1-6	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-hexyl)-acid amides]; 1H-NMR(400MHz，(CH 3) 2SO)：δ＝ 9.75(s，1H)，8.31(d，J＝8.6Hz， 1H)，7.91(m，1H)，7.78(m，1H)， 7.14(m，1H)，6.98(m，1H)，6.78 (m，1H)，6.59(m，1H)，4.93(s，2H)， 3.95(m，1H)，1.57-1.41(m，2H)， 1.34-1.22(m，6H)，1.14(d，J＝6.6 Hz，3H)，0.86(t，J＝6.8Hz，3H)	360.17	360.3
				1-7	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles heptamide	358.16	358.2
1-8	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-diisopropylaminoethyl ethyl)-acid amides]	389.20	389.3
				1-9	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-methoxyl group-propyl group)-acid amides]	334.12	334.2
1-10	Thiophene-2,5-dicarboxylic acid 2-[(2-kharophen ethyl)-acid amides] 5-[(2-amino-hexyl)-acid amides]	347.12	347.2

1-11	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-ethyl-hexyl)-acid amides]	374.19	374.2
				1-12	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-cyclooctylamine	372.17	372.2
1-13	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1,5-dimethyl-hexyl)-acid amides]	374.19	374.2
				1-14	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles valeramide	330.13	330.2
1-15	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methoxyl group-1-methyl-ethyl)-acid amides]	334.12	334.2
				1-16	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-cyclopropyl methyl-acid amides	316.11	316.2
1-17	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dimethylamino-2, the 2-dimethyl propyl)-acid amides]	375.19	375.2
				1-18	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-dimethylaminoethyl)-acid amides]; 1H-NMR(400MHz，(CH 3) 2SO)：δ＝ 9.84(s，1H)，8.84(t，J＝5.6Hz， 1H)，7.96(m，1H)，7.74(m，1H)， 7.12(m，1H)，6.99(m，1H)，6.78 (m，1H)，6.59(m，1H)，4.96(s，2H)， 3.57(m，2H)，3.19(m，2H)，2.80(s， 6H)；	333.14	333.2
1-19	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(butyl-methyl-acid amides)	332.14	332.3
				1-20	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-valeramide	332.14	332.2
1-21	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-butyramide	318.13	318.2
				1-22	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-{[3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-acid amides }	387.15	387.1
1-23	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-oxyethyl group-propyl group)-acid amides]	348.14	348.2
				1-24	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-second month in a season-butyramide; 1H-NMR(400 MHz，(CH 3) 2SO)：δ＝9.77(s，1H)，	318.13	318.2

	8.32(d，J＝8.1Hz，1H)，7.92(m， 1H)，7.80(m，1H)，7.13(m，1H)， 6.98(m，1H)，6.78(m，1H)，6.59 (m，1H)，4.94(s，2H)，3.87(m，1H)， 1.59-1.44(m，2H)，1.15(d，J＝ 6.6Hz，3H)，0.87(t，J＝7.3Hz，3H)
				1-25	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-heptamide	360.17	360.2
1-26	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-pelargonamide	388.21	388.3
				1-27	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-decoylamide	374.19	374.3
1-28	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(1-methyl-heptyl)-acid amides]	374.19	374.3
				1-29	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(isobutyramide)	318.13	318.2
1-30	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-Propargyl-acid amides	300.08	300.1
				1-31	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-propionic acid amide	304.11	304.2
1-32	Thiophene-2,5-dicarboxylic acid 2-allyl group acid amides 5-[(2-amino-phenyl)-acid amides]	302.10	302.2
				1-33	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles butyramide	316.11	316.2
1-34	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-diethylamide	318.13	318.2
				1-35	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methyl-butyl)-acid amides]; 1H-NMR(400MHz，(CH 3) 2SO)：δ＝ 9.79(s，1H)，8.61(t，J＝5.8Hz，1H)， 7.93(m，1H)，7.77(m，1H)，7.12 (m，1H)，6.99(m，1H)，6.78(m， 1H)，6.59(m，1H)，4.95(s，2H)， 3.21-3.15(m，1H)，3.08-3.02(m， 1H)，1.67-1.57(m，1H)， 1.46-1.36(m，1H)，1.17-1.07(m， 1H)，0.89(t，J＝7.3Hz，3H)，0.86(d，J ＝6.6Hz，3H)	332.14	332.2
1-36	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-Propargyl-acid amides)	314.10	314.1

1-37	Thiophene-2,5-dicarboxylic acid 2-(allyl group-methyl-acid amides) 5-[(2-amino-phenyl)-acid amides]	316.11	316.3
				1-38	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-dimethylaminoethyl)-ethyl-acid amides]	361.17	361.2
1-39	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-dipropyl acidamide	346.16	346.2
				1-40	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-amyl group-acid amides)	346.16	346.2
1-41	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-diethyllaminoethyl)-methyl-acid amides]	375.19	375.3
				1-42	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-[is two-(2-methoxyl group-ethyl)-acid amides]	378.15	378.1
1-43	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(cyclopropyl methyl-propyl group-acid amides)	358.16	358.2
				1-44	Thiophene-2,5-dicarboxylic acid 2-acid amides 5-[(2-amino-phenyl)-acid amides]	262.07	262.2

Embodiment 2

The preparation of general formula I-B compound

Step 1: 6-(2-diisopropylaminoethyl-ethylamino formyl radical)-nicotinic acid methyl ester

1.1g (5mmol) 5-methoxycarbonyl-pyridine-2-potassium formiate, 0.9ml (12mmol) thionyl chloride and the suspension of 0.1ml DMF in the 5ml methylene dichloride are heated 2h under reflux state.In this reaction mixture, add 5ml CH ₂Cl ₂And evaporating solvent.This step is repeated 3 times.Resistates is suspended in 5ml CH ₂Cl ₂In and at ice-cooled 9.95ml (5.5mmol) 2-diethyl third aminoethyl, 0.97ml (7mmol) triethylamine, the 0.1ml DMF of adding down at 5ml CH ₂Cl ₂In solution.After under rt, stirring 12h, water, 5% citric acid and NaHCO ₃The extraction with aqueous solution organic phase is also used dried over mgso.Behind evaporating solvent, make resistates carry out obtaining 1.15g (3.7mmol) 6-(2-diisopropylaminoethyl-ethylamino formyl radical)-nicotinic acid methyl ester according to silica gel chromatography (triethylamine of 20%MeOH and 1% in ethyl acetate); Definite calculated value MW[M+H]: 308.20; MW measured value [M+H]: 308.20.

Step 2: 6-(2-diisopropylaminoethyl-ethylamino formyl radical)-nicotinic acid

The NaOH aqueous solution that in 1100mg (3.6mmol) 6-(2-diisopropylaminoethyl-ethylamino the formyl radical)-solution of nicotinic acid methyl ester in 10ml THF and 3.0ml MeOH, adds 3.6ml 2N.Under rt behind the 4h, evaporating solvent.With 1N HCl acidifying resistates, filter out and wash with water and obtain 936mg (3.2mmol) 6-(2-diisopropylaminoethyl-ethylamino formyl radical)-nicotinic acid; Definite MW[M+H] calculated value: 294.18; MW measured value [M+H]: 209.15.

Step 3: pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-diisopropylaminoethyl-ethyl)-acid amides] compound (2-1)

936mg (3.2mmol) 6-(2-diisopropylaminoethyl-ethylamino formyl radical)-nicotinic acid and the solution of 518mg (3.2mmol) N,N'-carbonyldiimidazole in 8ml THF are heated 1h down and are cooled to rt then at 45 ℃.Add 1.38g (12.8mmol) phenylenediamine and 0.5ml (6.4mmol) trifluoroacetic acid and under rt, stir 20h.Evaporating solvent also adds ammonia soln in resistates.Use CH ₂Cl ₂Extract water and evaporating solvent from the organic phase that merges.Make resistates carry out silica gel chromatography (ethyl acetate, the triethylamine of 20%MeOH and 1% in ethyl acetate) then and obtain 404mg (1.06mmol) pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-diisopropylaminoethyl-ethyl)-acid amides]; Definite MW[M+H] calculated value: 384.24; MW measured value [M+H]: 384.23.

Prepared following compounds according to the method described in the embodiment 2 step 1-3.

Sequence number	Title	Calculated value MW (M+H)	Measured value MW (M+H)
				2-1	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-diisopropylaminoethyl-ethyl)-acid amides]; 1H-NMR(400MHz， (CH 3) 2SO)：δ＝9.93(s，1H)，9.16 (m，1H)，8.84(t，J＝5.8Hz，1H)， 8.50(m，1H)，8.15(m，1H)，7.17 (m，1H)，6.99(m，1H)，6.78(m， 1H)，6.59(m，1H)，5.2(s，2H)， 3.29(m，2H)，3.00(m，2H)，2.58(t， J＝7.3Hz，2H)，0.99(d，J＝6.6Hz， 12H)	384.24	384.2
2-2	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-hexyl acid amides	341.20	341.2
				2-3	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(butyl-methyl-acid amides)	327.18	327.2
2-4	Pyridine-2,5-dicarboxylic acid 2-allyl group acid amides 5-[(2-amino-phenyl)-acid amides]	297.14	297.2
				2-5	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-benzene	367.21	367.2

	Base)-and acid amides] the 2-cyclooctylamine
				2-6	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(3-dibutylamino-propyl group)-acid amides]	426.29	426.3
2-7	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-methoxyl group-ethyl)-acid amides]	315.15	315.1
				2-8	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(3-butoxy-propyl group)-acid amides]	371.21	371.3
2-9	{ [5-(2-amino-phenyl amino formyl radical)-pyridine-2-carbonyl]-amino }-methyl acetate	329.12	329.1
				2-10	3-{[5-(2-amino-phenyl amino formyl radical)-pyridine-2-carbonyl]-amino }-the propionic acid tert-butyl ester	385.19	385.3
2-11	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2,2,3,3,3-five fluoro-propyl group)-acid amides]	389.10	389.1
				2-12	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2,2,3,3,4,4,4-seven fluoro-butyl)-acid amides]	439.10	439.1
2-13	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(1,5-dimethyl-hexyl)-acid amides]	369.23	369.3
				2-14	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-dipropyl acidamide	341.20	341.3
2-15	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(1-methyl-hexyl)-acid amides]	355.21	355.4
				2-16	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(methyl-amyl group-acid amides)	341.20	341.2
2-17	Pyridine-2,5-dicarboxylic acid 2-(allyl group-methyl-acid amides) 5-[(2-amino-phenyl)-acid amides]	311.15	311.3
				2-18	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-and acid amides] 2-[is two-(2-methoxyl group-ethyl)-acid amides]	373.19	373.3
2-19	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-[(2-diethyllaminoethyl)-methyl-acid amides]	370.22	370.4
				2-20	Pyridine-2,5-dicarboxylic acid 2-[(2-kharophen	342.16	342.1

	Ethyl)-and acid amides] 5-[(2-amino-phenyl)-acid amides]
				2-21	Pyridine-2,5-dicarboxylic acid 2-(allyl group-cyclopentyl-acid amides) 5-[(2-amino-phenyl)-acid amides]	365.45	365.3
2-22	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(cyclopropyl methyl-propyl group-acid amides)	353.44	353.3
				2-23	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-second month in a season-butyramide	313.38	313.23
2-24	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-dimethylamino-ethyl)-acid amides]	328.39	328.16

Embodiment 3

The preparation of general formula I-C compound

According to described in the embodiment 1 similarly mode and use known method described in document (standard textbook for example, such as Houben-Weyl, " Methoden der Organischen Chemie, Georg Thieme Verlag ', Stuttgart; Organic Reactions, John Wiley ﹠amp; Sons, Inc., New York) the preparation following compounds:

Sequence number	Title	Calculated value MW (M+H)	Measured value MW (M+H)
				3-1	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-diisopropylaminoethyl-ethyl)-acid amides]; 1H-NMR(400MHz， (CH 3) 2SO)：δ＝10.1(s，1H)，9.09 (m，1H)，8.77(t，J＝5.3Hz，1H)， 8.41(m，1H)，8.22(m，1H)，7.47 (m，1H)，6.97(m，1H)，6.83(m， 1H)，6.65(m，1H)，4.92(s，2H)， 3.27-3.23(m，2H)，2.99(m，2H)， 2.56(t，J＝7.3Hz，2H)，0.99(d， J＝6.6Hz，12H)；	384.24	384.2
3-2	Pyridine-2,5-dicarboxylic acid 5-allyl group acid amides 2-[(2-amino-phenyl)-acid amides]	297.14	297.2
				3-3	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-benzene	341.20	341.3

	Base)-and acid amides] 5-hexyl acid amides
				3-4	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-cyclooctylamine	367.21	367.3
3-5	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-dimethylamino-ethyl)-acid amides]; 1H-NMR(400MHz， (CH 3) 2SO)：δ＝10.11(s，1H)， 9.09(m，1H)，8.77(t，J＝5.3Hz， 1H)，8.41(m，1H)，8.22(m，1H)， 7.48(m，1H)，6.97(m，1H)，6.83 (m，1H)，6.66(m，1H)，4.91(s， 2H)，3.41(m，2H)，2.44(t， J＝6.8Hz，2H)，2.20(s，6H)	328.18	328.2
				3-6	Pyridine-2,5-dicarboxylic acid 5-[(2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides] 2-[(2-amino-phenyl)-acid amides]	342.16	342.2
3-7	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,2,3,3,3-five fluoro-propyl group)-acid amides]	389.10	389.1
				3-8	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,2,3,3,4,4,4-seven fluoro-butyl)-acid amides]	439.10	439.1
3-9	3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-ethyl butyrate	371.17	371.2
				3-10	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-hydroxyl-propyl group)-acid amides]	315.15	315.2
3-11	2-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-3-methyl-methyl-butyrate	371.17	371.2
				3-12	3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-ethyl propionate	357.16	357.1
3-13	{ [6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-methyl acetate	329.12	329.1
				3-14	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methoxyl group-ethyl)-acid amides]	315.15	315.1

3-15	2-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-4-methyl sulfane base-methyl-butyrate	403.14	403.1
				3-16	3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-the propionic acid tert-butyl ester	385.19	385.3
3-17	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,3-dihydroxyl-propyl group)-acid amides]	331.14	331.2
				3-18	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-butoxy-propyl group)-acid amides]	371.21	371.3
3-19	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-diethylin-1-methyl-butyl)-acid amides]	398.26	398.3
				3-20	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dibutylamino-propyl group)-acid amides]	426.29	426.3
3-21	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-second month in a season-butyramide	313.17	313.2
				3-22	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1,5-dimethyl-hexyl)-acid amides]	369.23	369.3
3-23	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(butyl-methyl-acid amides)	327.18	327.3
				3-24	Pyridine-2,5-dicarboxylic acid 5-(allyl group-methyl-acid amides) 2-[(2-amino-phenyl)-acid amides]	311.15	311.3
3-25	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-Propargyl-acid amides)	309.14	309.1
				3-26	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-[is two-(2-methoxy ethyl)-acid amides]	373.19	373.2
3-27	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-amyl group-acid amides)	341.20	341.2
				3-28	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(cyclopropyl methyl-propyl group-acid amides)	353.20	353.2

3-29	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-dipropyl acidamide	341.20	341.3
				3-30	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-diethyllaminoethyl)-methyl-acid amides]	370.22	370.4
3-31	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-hexyl)-acid amides]	355.21	355.3
				3-32	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-hydroxyl-ethyl)-acid amides]	301.32	301.13
3-33	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-{[2-(2-hydroxyl-oxyethyl group)-ethyl]-acid amides }	345.38	345.13
				3-34	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-cyclohexyl methyl-2-hydroxyl-ethyl)-acid amides]	397.5	397.15
3-35	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-hydroxyl-butyl)-acid amides]	329.38	329.11
				3-36	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methylol-2-methyl-butyl)-acid amides]	357.43	357.15
3-37	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-hydroxyl-cyclohexyl)-acid amides]	355.42	355.13
				3-38	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(2-[pair-(2-hydroxyl-ethyl)-amino]-ethyl }-acid amides)	388.45	388.2
3-39	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-dimethylamino-ethyl)-ethyl-acid amides]	356.45	356.3

Embodiment 4

The preparation of general formula I-D compound

According to described in the embodiment 1 similarly mode prepare paraphenylene terephthalamide's sulfonamide derivatives of general formula I-D:

Sequence number	Title	Calculated value MW (M+H)	Measured value MW (M+H)
				4-1	N-(2-amino-phenyl)-N '-(2-diisopropylaminoethyl-ethyl)-terephthalamide; 1H-NMR(400MHz， (CH 3) 2SO)：δ＝9.77(s，1H)， 8.54(t，J＝5.3Hz，1H)，8.06 (m，1H)，7.95(m，2H)，7.18 (m，1H)，6.99(m，1H)，6.79 (m，1H)，6.60(m，1H)，4.94(s， 2H)，3.23(m，2H)，2.98(m， 2H)，2.54(t，J＝7.3Hz，2H)， 0.99(d，J＝6.6Hz，12H)	383.24	383.3
4-2	N-(2-amino-phenyl)-N '-(3-dibutylamino-propyl group)-terephthalamide	425.29	425.3
				4-3	N-(2-amino-phenyl)-N '-(4-diethylin-1-methyl-butyl)-terephthalamide	397.26	397.2
4-4	N-(2-amino-phenyl)-N '-(3-diethylin-propyl group)-terephthalamide	369.23	369.3
				4-5	N-(2-amino-phenyl)-N '-(2-methoxyl group-1-methyl-ethyl)-terephthalamide	328.17	328.2
4-6	N-(2-amino-phenyl)-N '-cyclopropyl methyl-terephthalamide	310.16	310.2
				4-7	N-(2-amino-phenyl)-N '-(3-oxyethyl group-propyl group)-terephthalamide	342.18	342.3
4-8	N-(2-amino-phenyl)-N '-(2-dimethylamino-ethyl)-terephthalamide	327.18	327.3
				4-9	N-(2-amino-phenyl)-N '-[3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-terephthalamide	381.19	381.3
4-10	N-(2-amino-phenyl)-N '-(3-dimethylamino-2,2-dimethyl-propyl group)-terephthalamide	369.23	369.3
				4-11	N-allyl group-N '-(2-amino-phenyl)-terephthalamide	296.14	296.2
4-12	N-(2-amino-phenyl)-N '-butyl-right	312.17	312.2

	Benzenedicarboxamide
				4-13	N-(2-amino-phenyl)-N '-butyl-N '-methyl-terephthalamide	326.19	326.3

Embodiment 5

The preparation of general formula I-E compound

According to similar mode and use corresponding feedstock production following compounds described in the embodiment 1 step 1-4:

Sequence number	Title	Calculated value MW (M+H)	Measured value MW (M+H)
				5-1	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methoxyl group-acid amides)	292.08	292.2
5-2	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(oxyethyl group-acid amides)	306.09	306.1
				5-3	Thiophene-2,5-dicarboxylic acid 2-(allyloxy-acid amides) 5-[(2-amino-phenyl)-acid amides]; 1H-NMR(400MHz， (CH 3) 2SO)：δ＝11.90(s，1H)， 9.82(m，1H)，7.93(m，1H)， 7.78(m，1H)，7.65(m，1H)， 7.12(m，1H)，6.99(m，1H)， 6.78(m，1H)，6.59(m，1H)， 6.05-5.95(m，1H)，5.39-5.35(m， 1H)，5.30-5.28(m，1H)，4.95(s， 2H)，4.42(d，J＝6.1Hz，1H)	318.09	318.2
5-4	Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(phenoxy group-acid amides)	354.09	354.2
				5-5	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-oxyamide; 1H-NMR(400MHz， (CH 3) 2SO)：δ＝11.61(s，1H)， 10.12(s，1H)，9.36(s，1H)， 9.02(m，1H)，8.35(m，1H)， 8.21(m，1H)，7.47(m，1H)， 6.97(m，1H)，6.83(m，1H)， 6.66(m，1H)，4.94(s，2H)	273.10	273.2
5-6	Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-oxyamide	273.10	273.1

5-7	Pyridine-2,6-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 6-oxyamide	273.10	273.1
				5-8	Pyridine-2,4-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 4-oxyamide	273.10	273.1
5-9	Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(uncle-butoxy-acid amides)	334.41	334.2

Embodiment 6

A) tablet (wet granulation):

Project component mg/ sheet

1. 5 25 100 500 of general formula I or A

Compound

2. lactose hydrous DTG 125 105 30 150

3. Sta-Rx1500 6 6 6 30

4. Microcrystalline Cellulose 30 30 30 150

5. Magnesium Stearate 1111

Amount to 167 167 167 831

Preparation process:

1. mix the 1st, 2,3 and 4 and use pure water to granulate.

2. at 50 ℃ of following dried particles.

3. particle is passed through suitable grinding plant.

4. add the 5th and mixed 3 minutes; On suitable tabletting machine, suppress.

B) capsule:

Project component mg/ capsules

1. the chemical combination 5 25 100 500 of general formula I or A

Thing

2. lactose hydrous 159 123 148---

3. W-Gum 25 35 40 70

4. talcum 10 15 10 25

5. Magnesium Stearate 1225

Amount to 200 200 300 600

Preparation process

1. in suitable mixing tank, the 1st, 2 and 3 was mixed 30 minutes.

2. add the 4th and 5 and mixed 3 minutes.

3. be packed into examples of suitable.

Can further estimate the effect of The compounds of this invention by following test:

Method

To the age is male NMRI nu/nu-mouse (n=15/ group) the subcutaneous injection 5*10 in 8-10 week ⁶The PC-3 prostate cancer cell.In the time of the 10th day, will have about 150mm ³The animal of gross tumor volume is randomized into the treatment group.With test compounds as at 7,5% gelatin-0, the little suspension among the 22%NaCl-contain little suspension administration based on the 10ml/kg applied volume of ABW.Began to be undertaken once a day from about the 10th day by the 27th day, based on the oral administration of 5-7 treatment plan weekly.

Determine gross tumor volume according to following equation:

Gross tumor volume=1/2ab ², wherein " a " and " b " is respectively the length and the short diameter of tumour.

Reference list

DE-A 2 062 265；

EP-A 0 242 851；

EP-A 0 847 992；

EP 0 974 576；

FR 2 167 954；

Hassan, H. etc., Indian J.Chem.39B (2000) 764-768;

Holba, V. etc., Z.Phys.Chem.262 (1981) 445-448

Houben-Weyl; " Methoden der organischen Chemie " Band XV/1 and XV/2;

Koyama, Y. etc., Blood 96 (2000) 1490-1495;

Moll, R. etc., Z.Chem.17 (1977) 133-134;

Rastogi, R., and Sharma, S., Indian J.Chem., Sect.B, 21B (5) (1982) 485-487;

US 2,680,731；

WO 93/21146。

Claims (65)

1. the compound of general formula A and pharmacy acceptable salt thereof:

Wherein:

Ar is a thiophene-2,5-two bases, pyridine-2,5-two bases, pyridine-5,2-two bases, pyridine-2,6-two bases, pyridine-2,4-two bases or 1,4-phenylene;

R ¹, R ²Represent hydrogen, C independently of one another _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, C _3-12-cycloalkyl, described alkyl, alkenyl, alkynyl and cycloalkyl are optional by hydroxyl, halogen, C _3-12-cycloalkyl, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; Or alternatively

R ¹Be hydrogen; And

R ²Be hydroxyl, alkoxyl group, C ₂-C ₁₂-alkenyloxy or phenoxy group, this phenoxy group optional by methyl, methoxyl group, halogen, nitro, cyano group, trifluoromethyl, vinyl or-C (O)-O-CH ₃Replace,

Condition is if R ²Be hydroxyl, Ar is not a thiophene-2 so, 5-two bases; And

R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl; Or wherein

R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

2. the compound of the general formula I of claim 1 and pharmacy acceptable salt thereof:

General formula I

Wherein:

Ar is a thiophene-2,5-two bases, pyridine-2,5-two bases, pyridine-5,2-two bases or 1,4-phenylene; R ¹, R ²Represent hydrogen, C independently of one another _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, C _3-12-cycloalkyl, described alkyl, alkenyl, alkynyl and cycloalkyl are optional by hydroxyl, halogen, C _3-12-cycloalkyl, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted;

R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl; Or wherein

R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

3. the compound of the general formula I of claim 2, wherein R ¹Be hydrogen or alkyl and R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As defined in claim 2.

4. the compound of the general formula I of claim 2, wherein R ¹Be hydrogen and R ²Be alkenyl or alkynyl.

5. the compound of the general formula I of claim 2, wherein R ¹Be hydrogen and R ²Be unsubstituted straight or branched C _1-12-alkyl or alkoxy, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

6. the compound of the general formula I of claim 2, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted C _1-12-alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

7. the compound of the general formula I of claim 2, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

8. the compound of the general formula I of claim 2, wherein R ¹Be hydrogen or alkyl and R ²Be cycloalkyl or the alkyl that is substituted by cycloalkyl.

9. the compound of claim 2, wherein Ar is the thiophene-2 of following general formula, 5-two bases:

R wherein ¹And R ²As defined in claim 2.

10. the compound of claim 9, wherein R ¹Be hydrogen or C _1-6-alkyl; And R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As defined in claim 2.

11. the described compound of claim 10:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(butyl-methyl-acid amides);

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-diethylamide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-Propargyl-acid amides);

Thiophene-2,5-dicarboxylic acid 2-(allyl group-methyl-acid amides) 5-[(2-amino-phenyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-dimethylaminoethyl)-ethyl-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-dipropyl acidamide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-amyl group-acid amides);

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-diethyllaminoethyl)-methyl-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-[is two-(2-methoxyl group-ethyl)-acid amides]; Or

Thiophene-2,5-dicarboxylic acid 2-acid amides 5-[(2-amino-phenyl)-acid amides].

12. the described compound of claim 9, wherein R ¹Be hydrogen and R ²Be alkenyl or alkynyl.

13. the described compound of claim 12:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-Propargyl-acid amides; Or

Thiophene-2,5-dicarboxylic acid 2-allyl group acid amides 5-[(2-amino-phenyl)-acid amides].

14. the described compound of claim 9, wherein R ¹Be hydrogen and R ²Be unsubstituted straight or branched C _1-12-alkyl or alkoxy, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH--is single to be replaced or polysubstituted alkyl 2

15. the described compound of claim 14:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-butyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-hexyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-methoxyl group-propyl group)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-kharophen ethyl)-acid amides] 5-[(2-amino-phenyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-ethyl-hexyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1,5-dimethyl-hexyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methoxyl group-1-methyl-ethyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-valeramide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-butyramide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-oxyethyl group-propyl group)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-second month in a season-butyramide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-heptamide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-pelargonamide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-decoylamide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-heptyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(isobutyramide);

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-propionic acid amide; Or

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methyl-butyl)-acid amides].

16. the described compound of claim 9, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted C _1-12-alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

17. the example of this compounds is:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-diethylin-1-methyl-butyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-diethylin-propyl group)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dibutylamino-propyl group)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(3-dimethylamino-propyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-diisopropylaminoethyl ethyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dimethylamino-2, the 2-dimethyl propyl)-acid amides]; Or

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-dimethylaminoethyl)-acid amides].

18. the described compound of claim 9, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

19. the described compound of claim 18:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-{[3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-acid amides }.

20. the described compound of claim 9, wherein R ¹Be hydrogen or alkyl and R ²Be cycloalkyl or the alkyl that is substituted by cycloalkyl.

21. the described compound of claim 20:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles heptamide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-cyclooctylamine;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles valeramide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-encircles butyramide;

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(cyclopropyl methyl-propyl group-acid amides); Or

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-cyclopropyl methyl-acid amides.

22. the described compound of claim 2, wherein Ar is the pyridine-2 of following general formula I-B, 5-two bases:

Wherein:

R ¹Be hydrogen or alkyl; And

R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As above-mentioned definition.

23. the described compound of claim 22:

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(butyl-methyl-acid amides);

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-dipropyl acidamide;

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(methyl-amyl group-acid amides);

Pyridine-2,5-dicarboxylic acid 2-(allyl group-methyl-acid amides) 5-[(2-amino-phenyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-and acid amides] 2-[is two-(2-methoxyl group-ethyl)-acid amides]; Or

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-[(2-diethyllaminoethyl)-methyl-acid amides].

24. the described compound of claim 22, wherein R ¹Be hydrogen and R ²Be alkenyl or alkynyl.

25. the described compound of claim 24:

Pyridine-2,5-dicarboxylic acid 2-allyl group acid amides 5-[(2-amino-phenyl)-acid amides].

26. the described compound of claim 22, wherein R ¹Be hydrogen and R ²Be unsubstituted straight or branched C _1-12-alkyl or by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

27. the described compound of claim 26:

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-hexanamide;

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-methoxyl group-ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(3-butoxy-propyl group)-acid amides];

{ [5-(2-amino-phenyl amino formyl radical)-pyridine-2-carbonyl]-amino }-methyl acetate;

3-{[5-(2-amino-phenyl amino formyl radical)-pyridine-2-carbonyl]-amino }-the propionic acid tert-butyl ester;

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2,2,3,3,3-five fluoro-propyl group)-acid amides];

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2,2,3,3,4,4,4-seven fluoro-butyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(1,5-dimethyl-hexyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(1-methyl-hexyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-kharophen ethyl)-acid amides] 5-[(2-amino-phenyl)-acid amides].

28. the described compound of claim 22, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

29. the described compound of claim 28:

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-diisopropylaminoethyl-ethyl)-acid amides]; Or

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(3-dibutylamino-propyl group)-acid amides].

30. the described compound of claim 22, wherein R ¹Be hydrogen and R ²Be cycloalkyl.

31. the described compound of claim 30:

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-cyclooctylamine.

32. the described compound of claim 2, wherein Ar is the pyridine-5 of following general formula I-C, 2-two bases:

Wherein:

R ¹Be hydrogen or alkyl; And

R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As above-mentioned definition.

33. the described compound of claim 32:

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(butyl-methyl-acid amides);

Pyridine-2,5-dicarboxylic acid 5-(allyl group-methyl-acid amides) 2-[(2-amino-phenyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-Propargyl-acid amides);

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-and acid amides] 5-[is two-(2-methoxy ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methyl-amyl group-acid amides);

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-dipropyl acidamide; Or

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-[(2-diethyllaminoethyl)-methyl-acid amides].

34. the described compound of claim 32, wherein R ¹Be hydrogen and R ²Be alkenyl or alkynyl.

35. the described compound of claim 34:

Pyridine-2,5-dicarboxylic acid 5-allyl group acid amides 2-[(2-amino-phenyl)-acid amides].

36. the described compound of claim 32, wherein R ¹Be hydrogen and R ²For unsubstituted alkyl or by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

37. the described compound of claim 36:

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-hexanamide;

Pyridine-2,5-dicarboxylic acid 5-[(2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides] 2-[(2-amino-phenyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,2,3,3,3-five fluoro-propyl group)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,2,3,3,4,4,4-seven fluoro-butyl)-acid amides];

3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-ethyl butyrate;

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-hydroxyl-propyl group)-acid amides];

2-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-3-methyl-methyl-butyrate;

3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-ethyl propionate;

{ [6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-methyl acetate;

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-methoxyl group-ethyl)-acid amides];

2-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-4-methyl sulfane base-methyl-butyrate;

3-{[6-(2-amino-phenyl amino formyl radical)-pyridine-3-carbonyl]-amino }-the propionic acid tert-butyl ester;

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2,3-dihydroxyl-propyl group)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-butoxy-propyl group)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-second month in a season-butyramide;

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1,5-dimethyl-hexyl)-acid amides]; Or

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-methyl-hexyl)-acid amides].

38. the described compound of claim 32, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

39. the described compound of claim 38:

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-diisopropylaminoethyl-ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-dimethylamino-ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-diethylin-1-methyl-butyl)-acid amides]; Or

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(3-dibutylamino-propyl group)-acid amides].

40. the described compound of claim 32, wherein R ¹Be hydrogen or alkyl and R ²Be cycloalkyl.

41. the described compound of claim 40:

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-cyclooctylamine; Or

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(cyclopropyl methyl-propyl group-acid amides).

42. the described compound of claim 2, wherein Ar represents 1,4-phenylene, the i.e. compound of general formula I-D:

Wherein:

R ¹Be hydrogen or alkyl; And

R ²Be hydrogen, C _1-12-alkyl, C _2-12-alkenyl, C _2-12-alkynyl, described alkyl, alkenyl and alkynyl are optional by hydroxyl, halogen, alkoxyl group, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-, C _1-6-alkyl-C (O) NH-or-NR ³R ⁴Single replacement or polysubstituted; R wherein ³R ⁴As above-mentioned definition.

43. the described compound of claim 42:

N-(2-amino-phenyl)-N '-butyl-N '-methyl-terephthalamide.

44. the described compound of claim 42, wherein R ¹Be hydrogen and R ²Be alkenyl or alkynyl.

45. the described compound of claim 44:

N-allyl group-N '-(2-amino-phenyl)-terephthalamide.

46. the described compound of claim 42, wherein R ¹Be hydrogen and R ²Be unsubstituted straight or branched alkyl or alkoxy, alkyl alkylthio base, acyloxy, carbalkoxy, acyl group, C _1-6-alkyl-NH-C (O)-or C _1-6-alkyl-C (O) NH-is single to be replaced or polysubstituted alkyl.

47. the described compound of claim 46:

N-(2-amino-phenyl)-N '-(2-methoxyl group-1-methyl-ethyl)-terephthalamide;

N-(2-amino-phenyl)-N '-(3-oxyethyl group-propyl group)-terephthalamide; Or

N-(2-amino-phenyl)-N '-butyl-terephthalamide.

48. the described compound of claim 42, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Represent hydrogen or C independently of one another _1-6-alkyl.

49. the described compound of claim 48:

N-(2-amino-phenyl)-N '-(2-diisopropylaminoethyl-ethyl)-terephthalamide,

N-(2-amino-phenyl)-N '-(3-dibutylamino-propyl group)-terephthalamide;

N-(2-amino-phenyl)-N '-(4-diethylin-1-methyl-butyl)-terephthalamide;

N-(2-amino-phenyl)-N '-(3-diethylin-propyl group)-terephthalamide;

N-(2-amino-phenyl)-N '-(2-dimethylamino-ethyl)-terephthalamide; Or

N-(2-amino-phenyl)-N '-(3-dimethylamino-2,2-dimethyl-propyl group)-terephthalamide.

50. the described compound of claim 42, wherein R ¹Be hydrogen and R ²Be quilt-NR ³R ⁴The single replacement or polysubstituted alkyl, wherein R ³And R ⁴Form ring with the nitrogen-atoms that they connected, this ring can be contained another heteroatoms by the single replacement of oxo and this ring.

51. the described compound of claim 50:

N-(2-amino-phenyl)-N '-[3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-terephthalamide.

52. the described compound of claim 42, wherein R ¹Be hydrogen, alkyl or alkenyl and R ²Be cycloalkyl or the alkyl that is substituted by cycloalkyl.

53. the described compound of claim 52:

N-(2-amino-phenyl)-N '-cyclopropyl methyl-terephthalamide.

54. the compound of the described general formula I-E of claim 1:

Wherein:

Ar is a thiophene-2,5-two bases, pyridine-2,5-two bases, pyridine-2,6-two bases, pyridine-2,4-two bases, pyridine-5,2-two bases or 1,4-phenylene; And

R ²Expression hydroxyl, alkoxyl group, C ₂-C ₁₂-alkenyloxy or phenoxy group,

Condition is if R ²Be hydroxyl, Ar is not a thiophene-2 so, 5-two bases.

55. the described compound of claim 54:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(methoxyl group-acid amides);

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(oxyethyl group-acid amides);

Thiophene-2,5-dicarboxylic acid 2-(allyloxy-acid amides) 5-[(2-amino-phenyl)-acid amides];

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(phenoxy group-acid amides);

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 5-oxyamide;

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-oxyamide;

Pyridine-2,6-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 6-oxyamide; Or

Pyridine-2,4-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] the 4-oxyamide.

56. claim 1 or 2 described compounds:

Thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(uncle-butoxy-acid amides);

Pyridine-2,5-dicarboxylic acid 2-(allyl group-cyclopentyl-acid amides) 5-[(2-amino-phenyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-(cyclopropyl methyl-propyl group-acid amides);

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] the 2-second month in a season-butyramide;

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-hydroxyl-ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-{[2-(2-hydroxyl-oxyethyl group)-ethyl]-acid amides };

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-cyclohexyl methyl-2-hydroxyl-ethyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-hydroxyl-butyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(1-hydroxymethyl-2-methyl-butyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(4-hydroxyl-cyclohexyl)-acid amides];

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-(2-[pair-(2-hydroxyl-ethyl)-amino]-ethyl }-acid amides);

Pyridine-2,5-dicarboxylic acid 5-[(2-amino-phenyl)-acid amides] 2-[(2-dimethylamino-ethyl)-acid amides]; Or

Pyridine-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-acid amides] 5-[(2-dimethylamino-ethyl)-ethyl-acid amides].

57. the method for any one compound among the preparation claim 1-56 is characterized in that:

(1) make the compound of general formula I I and the compound reaction of general formula III, wherein the structural formula of general formula I I compound is as follows:

Wherein Ar, R ¹And R ²As defined in claim 1, and R ²Can carry protecting group to prepare wherein R ²Described compound for hydroxyl;

Wherein the structural formula of compound of formula III is as follows:

Wherein Y represents hydrogen or suitable amino protecting group;

This reaction is carried out through the following steps: at first at the compound that activation general formula I I is arranged in the presence of the activator and add the compound of general formula III subsequently, if necessary, protecting group under the final cracking; Or

(2) make compound and the general formula HNR of general formula VI ¹R ²Amine reaction, the structural formula of its formula of VI compound is as follows:

Wherein Ar as defined in claim 1 and Y can carry protecting group described in (1);

At general formula HNR ¹R ²In, R ¹And R ²As defined in claim 1, and R ²Also can carry protecting group to prepare wherein R ²Described compound for hydroxyl; And if necessary, protecting group under the final cracking; With

(3) if desired, by adding suitable acid or alkali product is changed into pharmacy acceptable salt.

58. contain medicine just like any described one or more compounds and pharmaceutically acceptable vehicle among the claim 1-56.

59. the medicine of claim 58 is used to suppress tumor growth.

60. any one compound application in the treatment cancer among the claim 1-56.

61. any one compound is used for suppressing the application of the relative medicine of tumor growth among the claim 1-56 in preparation.

62. the medicine of claim 58 is used for the treatment of cancer.

63. be used to suppress the method for tumor growth, one or more compounds of one of claim 1-56 by making described tumour cell and significant quantity contact and carry out.

64. by method or equivalent processes as claim 57 described in prepare according to any one compound among the claim 1-56.

65. the present invention as indicated above.